TWiV 967 Clinical Update

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 24 December 2022

pdf of this transcript available (link)

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick.

[music]

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 967, recorded on December 22, 2022. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me from New York, Daniel Griffin.

DG: Hello, everyone.

VR: I’m glad to have you back because it was too noisy in Uganda.

DG: It was hard. [laughter] I have to say. That first night out there in the storm and trying to use my iPhone, and then the couple of other times when I was recording up in the mountains on the DRC border, a few kilometers away from where the ISIS insurgents came across the line.

VR: People do appreciate that you do this remotely. I think we couldn’t have done this five years ago probably. The tech wasn’t there, so it was really remarkable that we can do this. Anytime it’s fine. We can try it always because people need to keep up with their clinical information.

DG: I think Laurie Garrett and I were chatting when there was that event at The Incubator about one time she had some satellite uplink and things have gotten a little bit easier, so I shouldn’t complain. I’ll just die of malaria.

[laughter]

All right, let me get right into it. “No one is useless in this world who lightens the burdens of another.” That’s Charles Dickens. It seems to me that quoting Dickens works with so many celebrating Christmas throughout the world. This will drop, I guess, on Christmas Eve, so Merry Christmas to those of you celebrating. We are in the middle of Hanukkah, actually. For the youngest, who listen, I think we have some very young listeners, remember, it’s not like your birthday. Don’t blow out the candles.

All right. Let me start with an article, “Immunological Dysfunction Persists for 8 Months Following Initial Mild-to-Moderate SARS-CoV-2 Infection,” published in Nature Immunology. I have to say when I saw this title, I was like, “Oh, this may answer many questions.” Well, maybe not. This is a study where the title can be, I think, misleading. The investigators studied individuals with Long COVID compared to age and gender-matched recovered individuals without Long COVID, unexposed donors, and individuals infected with other coronaviruses. Apparently, they’re discussing and calling them the common coronaviruses, which I think we already do.

Anyway, patients with Long COVID have highly activated, innate immune cells, lacked naive T and B cells, and showed elevated expression of type I interferon, interferon beta, type III interferon λ1 that remained persistently high at eight months after infection. They report that they analyzed the cohort of individuals followed systematically for eight months after COVID-19 infection, according to a predefined schedule. Compared them to healthy donors unexposed to SARS-CoV-2, the unexposed healthy controls before December 2019 and individuals who had been infected with prevalent common cold, human coronaviruses, but not SARS-CoV-2.

They assessed 28 analytes in the serum, looked at matched controls, unexposed to healthy individuals. They did report that six pro-inflammatory cytokines and soluble T-cell immunoglobulin mucin domain-3 were elevated in the Long COVID, compared these to the other groups. I have to say I don’t think this data really gives us that compelling data that COVID immune dysfunction following infection explains this onslaught of respiratory viral infections we’re suffering through.

I did also get some communications. We talked about Sweden suggesting that there may have been more significant voluntary behavior changes that suggest. I’m still leaving a lot open to explain why are we getting such a deluge of respiratory issues.

Along those lines, influenza has taken over, but we are now, I hope, reinforcing that. Ockham was not a physician, and a patient can have as many diseases as they darn well please.

El MMWR release, “Prevalence of SARS-CoV-2 and Influenza Coinfection, and Clinical Characteristics among Children and Adolescents Aged Less Than 18 Years Who Were Hospitalized or Died with Influenza, United States, 2021 through 2022 Influenza Season,” really reinforces this, saying, they report that during the 2021-2022 influenza season, 6%, so a little bit more than 1 in 20, hospitalized pediatric influenza patients had SARS-CoV-2 co-infection. A higher percentage of patients with co-infection required invasive or non-invasive respiratory support compared with those with influenza only.

Among the influenza-associated pediatric deaths, yes, pediatric deaths, 16% had SARS-CoV-2 co-infection. Also, a higher proportion of patients with co-infection received mechanical ventilation. That was 13% versus 4. BiPAP or CPAP 16% versus 6. Forty-four influenza-associated pediatric deaths were reported to the influenza-associated pediatric mortality surveillance system, 16% of these folks SARS-CoV-2 co-infection, so were these flu deaths? Are they COVID deaths? They’re deaths, they are children that didn’t survive.

Continuing to see, it’s a warning to those who are getting together, that’s what human beings do, that we are seeing incredibly high influenza activity across the country. I think I was a joking with Brian Leher about being judgy about people getting together with wanton abandon. People get together during the holidays, so just a little bit more education, a little bit more information so people can make wise decisions.

Just a little primer here on influenza, we have really covered COVID in depth. People will be listening over the Christmas weekend. First, transmission big thing here is respiratory but also contact. Wash those hands. I know everyone loves to hug. Incubation period, the typical incubation period is pretty short, one to four days. Average is about two days. Clinical presentation, it’s a virus, so it presents like a- well, an influenza-like illness, but it actually is influenza so fever, malaise, cough, body aches. How do you diagnose this?

If you don’t do a test, you don’t know. This is going to be PCR, it’s going to be antigen testing, and actually treatment. We do have some options. Again, think about what we’ve talked about with COVID. Think about really identifying those people who are going to benefit starting the Tamiflu, the oseltamivir, within the first 48 hours of symptom onset. I will say, and then I’ll talk a little bit more about this next week as well, we are running short of medication for influenza.

The U.S. government is going to release extra doses from our strategic stockpile. This is something that, listen, if it’s a low-risk individual, they’re going to feel better a day sooner. Let’s make wise decisions about who benefits most. If you’ve got an older individual, grandma, grandpa, people that look Dickson with that white beard, if it’s Santa coming to town, he carries a little bit of extra weight, he would be the target population for the Tamiflu.

VR: Are we running out of antivirals, we haven’t got enough stockpiled?

DG: It’s interesting, isn’t it, that we’re running out of – Well, I have to say, this is the worst influenza season in over a decade when it comes to hospitalization. This is really hitting the system hard.

VR: More people are needing the antivirals so our normal supply is inadequate, basically.

DG: Exactly.

All right. COVID, is it too soon? Perhaps. People talk about how many people died during the 1918 flu pandemic. The estimates are so broad, perhaps in part because, when do we stop counting, when is the death part of the pandemic, when did that pandemic of 1918 actually end? The article, “The WHO Estimates of Excess Mortality Associated with the COVID-19 Pandemic,” was published in Nature.

Should they add at the end of the title, “so far?” Here they are reporting excess mortality, which they define as the difference in the total number of deaths in a crisis compared to those expected under normal conditions. They report an estimated 4.47 million excess deaths for India alone during the period of January 2020 to December 2021. That’s stopped about a year ago, followed by over one million excess deaths in the Russian Federation, over one million excess deaths in Indonesia, close to a million excess deaths in the United States.

In total, about 15 million excess deaths globally just during that period of time. Remember, this is excess, so the total number of COVID-19 deaths is actually higher. As I mentioned, so far because the deaths are continuing. I have to say, I’m always curious when I watch these comments on Twitter where people seem not to want to count COVID deaths, so interesting.

Right up front here I want to discuss the article, “Reconsideration of Anti-nuclear Capsid IgG Antibody as a Marker of SARS-CoV-2 Infection Post-Vaccination for M/ild COVID-19 Patients,” published in Open Forum Infectious Diseases. Is Rich Condit  listening? Rich, I’m going to send this to you. Eighty-two adult participants who, one, were enrolled in the outpatient SARS-CoV-2 mild and asymptomatic immune response and transmission – OutSMART – cohort after 2020-12-09. Two, had confirmed SARS-CoV-2 infection by nasopharyngeal/saliva RNA test. Three, were greater than or equal to 18 years old. Four, had at least one validated oral/ plasma antibody result. And, five, had mild COVID-19 with a reported date of symptom onset.

They found that while patients who were infected prior to vaccination who were never vaccinated maintained elevated anti-N IgG antibody responses. Those who were vaccinated prior to infection had significantly lower anti-N IgG responses, nice P value there. Mild COVID-19 patients, those with prior vaccination do not reliably induce robust anti-N IgG responses in plasma or oral fluid. Hence, the use of anti-N antibody responses as a surrogate for recent infection may not be reliable for COVID-19 surveillance.

VR: It’s very interesting that vaccination is obviously reducing the amount of virus replication so you’re not getting a good response to the nuclear capsid, which is the most abundant viral protein.

DG: I think it’s fascinating. I’ve been listening to immune, and I’ll give a plug for that several times as we go forward, but is this an example of that immune imprinting that original antigenic sin, what I call the butterfly effect, where this should be the immunodominant response, you should be targeting.

VR: Imprinting is not even relevant because it’s a conserved protein, it doesn’t change in the variants whatsoever, not significantly. I don’t know why. The only thing I can think of is that if you’re vaccinated you’re getting so much less reproduction that you don’t get a good antibody. Anyway, Daniel, what can you use for surveillance then? Because you need to use a serological test because PCR is too transient.

DG: This is hard, because is this that you’re just not getting enough response to get anti-N or in my mind, are you putting all your response towards the S because that’s what you saw before?

VR: Oh, that’s what you meant by imprinting.

DG: Yes, the imprinting. This is interesting because we want to do serology. We want to know what’s going on in prevalence. Can you do it post-vaccine? I think all of us thought, oh, of this is great. This will be like hepatitis, what we do there, we look at some. It may be over time. I had a pediatrician .I take care of up in Maine, who with his first vaccine, developed transverse myelitis, very temporal, so concerns there. He’s all worried, what will happen now that we don’t have Evusheld? What will happen, COVID is here to stay? My hope is, as we get farther and farther out, will he end up with a good anti-N anybody response? I don’t know. I think this is a challenge.

The other article right up front here, “Impact of SARS-CoV-2 Variants on Inpatient Clinical Outcomes,” published in CID. I’m always trying to get information on how much of the progress we are seeing is due to the virus changing versus the protection that our immune system provides from vaccination or surviving a prior infection. Here we get a look at data from five hospitals in the eastern United States with stratification by history of prior vaccination or infection.

They found that the risk for severe disease or death from Omicron patients compared to ancestral lineages was 0.94 with a 95% confidence interval of 0.78 to 1.1. Among Omicron and Delta infections, patients with history of vaccination are prior SARS-CoV-2 infection had half the risk of severe disease or death, but no significant outcome difference by variant. The risk of severe disease or death for unvaccinated patients with Omicron was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients with no difference between Delta and Omicron infections.

VR: How often, Daniel, did we hear about Omicron is a cold? This is the problem with making conclusions the first few weeks that a variant emerges by observation of hospitalization. Now you do the right studies and you find that they’re all – it’s crazy, isn’t it?

DG: It’s one of those things that, it’s frustrating, Vincent, because we’re going to see in China, unfortunately in China, there’s not a lot of immunity from prior infection. There’s unfortunately not a lot of immunity from vaccination in the highest risk population. As we’ve heard, the older individuals in mainland China are too frail to be vaccinated. Unfortunately, what we’re seeing here is that no, no, the virus did not become mild, what we’re seeing is vaccines work and so a vaccinated individual that gets infected with a virulent virus does a lot better than someone who doesn’t have immunity. I worry about that common wisdom, this idea that, oh, Omicron the virus has become so mild that now it’s just a head cold. No, what makes COVID mild is our immune system. That’s the science.

Children, COVID and other vulnerable populations. I’m going to change, I’m going to say, children are at risk from COVID and Long COVID. The article, “Clinical Features and Burden of Post-acute Sequelae of SARS-CoV-2 Infection in Children and Adolescents,” was published in Open Forum Infectious Diseases. In brief, they looked at, it was a retrospective cohort study using electronic health records from nine U.S. children’s hospitals for individuals less than 21 years of age who underwent PCR testing for SARS-CoV-2 between March 1, 2020 and October 31, 2021, and had at least one encounter in the three years before testing.

The reason they do that is so you have a baseline. They identified 659,286 children and 59,893 that tested positive by PCR for SARS-CoV-2. They reported an incident proportion difference, so the excess of 3.8%. A higher strength of association for PASC was identified in those cared for in the ICU during the acute illness phase, children less than 5, individuals with complex chronic conditions. A few, I think, important points. They’re reporting PASCt features in the 28-to-179 days following the initial test date.

There is an issue with the definition of PASC, how much of this resolves at 90 days or 12 weeks. Really just a reminder, this is something that was brought up in a recent discussion I had with a mom about why would we consider vaccinating her young children. It’s that children are at risk from COVID and Long COVID. Pre-exposure period, transmission, and testing, use those tests intelligently. Remember, there’s more out there than just COVID and have a plan. I was giving a talk for a major health system in New York that shall remain unnamed.

They talked about how we should just do the anterior nares instead of those deep brain biopsies, particularly in the children. I was told that the practice was still to do the deep swabs in the children. I suggested that rather than changing my talk, they should change their practice. Apparently, that was too challenging at the time but perhaps the article, “Similar SARS-CoV-2 CT Value Distributions in Anterior Nares versus Nasopharyngeal Samples from Symptomatic Children during Delta and Omicron Surges,” published in JPIDS is perhaps enough to move the needle, all there in the title for the surgeons, and a great figure for the PhDs.

VR: Daniel, if people are still giving antibiotics for COVID, this is not going to change the needle. I’m sorry.

DG: They keep sticking it all the way in there because that’s what I learned to do in April of 2020. I can’t move forward. I also want to say that there was a nice article by my friend Karen Weintraub, I think we’re friends at USA Today, alerting people to the fact that the White House has a plan and this includes, are you ready, this is going to solve everything, offering Americans four more free coronavirus tests per household.

Collaborating with communities to open pop-up or mobile vaccination sites, pre-positioning critical supplies like masks, gloves and gowns from the Strategic National Stockpile, providing more support to nursing homes and long-term care facilities to protect the most vulnerable. Well, interesting, so only four free coronavirus tests. That’s one for me, one for my wife, one for Daisy, one for Elise, sorry, Barnaby, I shouldn’t have had that third child. That will teach people not to have more than two children.

What about those other things? What support are they going to offer to nursing homes and long-term care facilities? Maybe some salary support so they can adequately staff the facilities with high quality staff?

All right. Masks, lots of concerns with the quality of studies, but in general, the science favors mask use and suggests a hierarchy with N95s offering the highest level of protection. If you’re feeling sick and you must go to that holiday gathering, consider wearing a mask. If you’re high risk, consider wearing a mask. Actually here in New York, I am seeing a little bit more mask use coming back. You don’t need a mandate. It doesn’t need to be required. You can actually be educated and make a smart decision.

Ventilation transmission, just reinforcing for the holidays that this is almost exclusively respiratory spread. Keep that HVAC fan turned to on, open a few windows, wear a sweater if it’s a little chilly and remember how much safer outdoors is from indoors. I’m a little worried about this. What is arctic or polar vortex or something that’s coming our way, so everyone will be crammed in together, breathing poor quality infected air.

VR: Winter that’s what happens, right, Daniel?

DG: Yes, it’s what happens. COVID active vaccination, lots to talk about this week with two MMWRs. We’ll talk about these, so let’s bring them up and then we’ll have a little discussion. Let me present the reports so we can discuss how to interpret the data. First, “Early Estimates” – and Very Early Estimates – “of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19 Associated Emergency Department or Urgent Care Encounters and Hospitalizations among Immunocompetent Adults, Vision Network, Nine States September-November, 2022.”

This is more data from the VISION Network where the effectiveness of bivalent booster doses among immunocompetent adults during September 13 through November 18, 2022, a period during which the Omicron BA.5 sublineage predominated was analyzed. Vaccine effectiveness in preventing COVID-19 associated emergency department or urgent care encounters and hospitalizations of a bivalent booster dose after two, three or four monovalent doses against hospitalization for COVID-19 associated illnesses was reported at 57% compared with no vaccination and 45% compared with receiver of last monovalent doses with last dose greater than or equal to 11 months earlier.

Want to point out among the adults who received a bivalent booster dose, the median interval since receive of the bivalent booster dose was 23 days. Remember you don’t start counting until it’s been like – and then you only count to 23. Second MMWR, so you really got a narrow window there to get infected. Second MMWR release, “Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalizations among Immunocompetent Adults Aged Greater than or Equal to 65 years, the IVY Network 18 states September 8-November 30, 2022,” gives us data from the IVY Network.

Here we get a report on the effectiveness of a bivalent booster dose received after greater than or equal to two doses of monovalent mRNA vaccine against COVID-19 associated hospitalizations among immunocompetent adults aged greater than equal to 65. This is a test negative design case control analysis of adults aged 65 or over admitted for COVID-19-like illness to any of 22 hospitals in 18 states participating in the Investigating Respiratory Viruses – IV – in the Acutely Ill Network. Again, the mean interval between receipt of a bivalent booster dose and illness was short at 29 days interquartile range of 15 to 45.

They report that when compared with patients whose last monovalent dose was six to 11 months and greater than or equal to 12 months before illness onset, relative vaccine effectiveness of bivalent booster dose was 78% and 83%. Small sample size precluded estimation of the relative vaccine effectiveness of bivalent booster dose compared with receipt of greater than or equal to two monovalent-only mRNA vaccine doses, with last dose two to five months before illness onset.

VR: Let me just make a few comments quickly. I will, because this is your show.

DG: No, I want you to make a few comments. I think this is important for us to discuss. I know Paul Offit waited a little so you can even channel him.

VR: I emailed Paul and asked for his thoughts and he agrees. The problem with this study is that there are multiple problems. First of all, the hospitalization. Paul agrees that you go in either with or because of COVID. It’s not clear that we’re distinguishing here and that’s a big deal. Hospitalization not a great metric. They’re comparing bivalent with historical monovalent old booster. They didn’t do an experiment where you give some people bivalent and some people the old booster.

If they did that, I think they would be the same. There’s no way to know that because they didn’t do that experiment. You can’t give people a booster, which is the original booster anymore. The reason I think it’s important is because if you could show that the old booster did the same thing as this one, you wouldn’t have to keep making new boosters every time a variant came around. I think those are important data to have.

Then finally, the last issue, these are 29 days from getting this bivalent booster. Of course, your antibody levels are high. Of course, you’re going to reduce everything. In two months or three months, that’s going to be gone. In my opinion, this doesn’t say anything positive about the bivalent boosters. As they say, it’s a very early analysis, but they shouldn’t have made headlines out of this. That’s not fair.

DG: I think I understand why they made headlines. The point you make, I think you and I are in same page here. One is, this is not unexpected that if you give someone a booster for a period of time, you’re going to have some degree of protection and we’ve talked about that. We’ve said like, let’s not over promise though. Are we talking about 21 days of protection that we’re counting because we don’t count for the first seven and then we count for 21.

There’s a political agenda. We want people to get boosted. We certainly want higher risk individuals to get boosted, but there’s a couple questions here. One is, this is not a study that says bivalent boosters are better than just getting boosted with the original. I think that’s really important, and actually, we really need the science on that. The other is this was done when BA.5 was dominant. What are we going to see now that we’re moving into other variants?

I think this gets a little sophisticated too. John Mascola and I were emailing a little bit as well. One of the concerns we have is, OK, now that when you get that booster, is it just boosting neutralizing antibodies? Is it boosting all antibodies? Is it boosting the rest of the immune system? I think a lot of this stuff, we need that information. That information is going to help us make good decisions in the future. What are these boosters actually boosting?

What are they boosting that really matters? I like a couple of the recent – I really like Immune, by the way, that’s my favorite podcast we do, even though I’m not on it. I liked Immune 62: “Every Cell is an Immune Cell, with De’Broski Herbert,” where there’s really a deeper dive into the complexities of the immune system. I’ve been emailing a bit with John Mascola, who was on TWiV 858 that I listened to while I was in West Africa.

I’m going to quote, “For a more general talk, for example, to medical residents, I sometimes use the analogy to an orchestra, the strings, woodwinds, brass and percussion can each make unique contributions and are pleasant to hear on their own, but together they take the listening experience to a new level.  Immunity works best when the immune system can call upon more than one component.” Also, I was listening to the most recent Immune and I emailed John Mascola. I said, “Did you email Vincent too, to tell him we should talk?”

I think that, I love that people listen to this update, but also I’m going to recommend people listen to IMMUNE as well. Just to point out, the immune system is so much more than getting a serology level, getting your antibody, your spike protein levels much more than just looking at neutralizing antibodies. I’ll carry John Mascola’s analogy to a higher level. It’s like looking at the orchestra and you notice one of the flute players is missing, but all the other flute players are still there. The horns are still there, and the strings are still there. I think sometimes we look at just levels of neutralizing antibodies. We forget about all the other Fc-mediated, other efficacies of our antibodies. We forget about the rest of the immune system. What do I take away from this? I’m not sure I can make much of this. Yes, there is going to be some period of time when you’re going to get enhanced protection. I would expect that. Will this enhanced protection work as the variants change? We will see, that will be interesting, how long will this protection last?

I guess the other, which is really that challenge is we need a better metric because it’s not just the COVID deniers that are having issues with using hospitalization as a metric. I think we’re all having an issue with using that as a metric. We need codes that tell us is this person being admitted with COVID, are they getting admitted for COVID, are they getting admitted for COVID with hypoxemia requiring oxygen. I think we need more information to sort this going forward.

We also learned that the FDA will, again, [chuckles] as independent advisors meet January 26th to discuss if the boosters need another update. Oh my Lord. Unless we want to lose ground going forward, we need to prioritize vaccine education. Hopefully, we’re helping with that. This really means that we need more resources put into communication, not some afterthought. Those folks that have been following Peter Hotez’s efforts for several years now may be aware that there is an organized, well-funded anti-science movement that is making a fortune of undermining vaccines and selling snake oil. They have really made progress, unfortunately, during the pandemic.

The Kaiser Family Foundation, “COVID-19 Vaccine Monitor Survey December 2022,” found that 71% say healthy children should be required to get vaccinated for MMWR in order to attend public schools down from 82%. We lost 11% there. Almost 3 in 10, 28% now say that parents should be able to decide not to vaccinate their school-aged children even if this creates health risk for others up from 16%. Among Republicans and Republican-leaning independents, there has been a 24 percentage point increase in this share who hold this view, from 20% up to 44%. Painful here.

We are losing the battle, by the way.

Let’s move forward to the COVID early viral, upper respiratory, non-hypoxic phase. More data on Paxlovid works, and Paxlovid rebound is not a thing. The article, “Effect of Nirmatrelvir/Ritonavir versus Placebo on COVID-19─Related Hospitalizations and Other Medical Visits,” published in Open Forum Infectious Diseases. These are the results of a phase 2/3 double-blind intervention study. Adults with confirmed SARS-C0V-2 and symptom onset less than or equal to five days were randomized one-to-one to receive, I’m just going to say Paxlovid or placebo orally every 12 hours for five days.

COVID-19-related medical visits were collected through day 28. Oxygen support for COVID-19 and details of COVID-19-related hospitalization, including duration, ICU status, and mechanical ventilation were assessed. Of the over 2,000 patients enrolled globally, fewer overall COVID-19-related medical visits were reported with Paxlovid versus placebo. In addition, I think it’s really important, to fewer hospitalizations being reported. This is 0.8% versus 6.2, so an 87% reduction patients receiving Paxlovid. The mean duration of days in hospital was 9.6 versus 11.2, so about two days shorter.

This is where it really gets important. No patients in the Paxlovid were admitted to the ICU, no patients who received Paxlovid required mechanical ventilation, and fewer patients required oxygen at all in the Paxlovid-treated group versus placebo, so less than 1% versus about 5%. Not only does it keep you out of the hospital, but if you do end up progressing, it’s really going to protect you from ending up on a ventilator.

Number two, remdesivir. Remember the early three-day therapy? Currently, nothing in the monoclonal box. Number four, molnupiravir. I’m going to say last and least, but maybe not because convalescent plasma. I have not talked about convalescent plasma in a while. Again, Rich Condit are you listening? Let me just share the preprint, [chuckles] “COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data from Five Randomized Trials,” posted on MedRX. They reported a 30% relative risk reduction for all-cause hospitalization. Really not much different than molnupiravir, which is just pills to take.

VR: Daniel, could you combine molnupiravir and convalescent plasma?

DG: You probably could and you could probably even combine molnupiravir and Paxlovid.

VR: Would you get additive protection?

DG: Well, I don’t know. I think, again, don’t try this at home without doing the science. It would be good to do the science and find out can we start adding these things, particularly, when you’re looking at those high-risk patients. You’ve got someone who’s got hematological malignancy, they’re on chemo, we’ve lost Evusheld, maybe they’re not responding as well to the vaccines or we wouldn’t expect them, do you do just Paxlovid or do you do Paxlovid and molnupiravir? Do you do Paxlovid and convalescent plasma? Actually, that’s a good point because I will say a couple things here.

The effect size was greatest in those with both early transfusion and high-titer, so not all convalescent plasma is the same. No significant reduction in hospitalization was seen with treatment after five days, so we have a small window there. Also, no significant reduction if that COVID-19 convalescent plasma had antibody titers below the median titers. Low titer just doesn’t do much.

Where do we stand? Because I know people have said, “Oh, convalescent plasma is recommended by the IDSA.” Well, let’s put a qualification there. Recommendation 19, among patients hospitalized with COVID-19, the IDSA recommends against strong recommendation. Recommendation 14, among ambulatory patients at high risk for progression of severe disease who have no other treatment options. I’m not sure that actually exists. Why would they not get molnupiravir? The IDSA panel suggests FDA-qualified high titer convalescent plasma. They say within eight days of symptom onset. We know that that window is probably smaller.

In the United States, the FDA EUA only authorizes use in patients with immunosuppressive disease or receiving immunosuppressive treatment. Patients, particularly those who are not immunocompromised, who place a low value on the uncertain benefits and a high value on avoiding possible adverse events associated with convalescent plasma would reasonably decline convalescent plasma, so not very compelling. Not a really large group of patients that would get targeted here.

The article, “Bacterial Co-infection and Empirical Antibiotic Therapy in Patients with COVID-19,” published in OFID. Retrospective study of 367 adult patients with a high rate of microbiological testing. They found the rate of bacterial co-infection in hospitalized patients was not 80%, like we’re seeing as far as usage, but confirmed in less than 10%, confirmed in only 8%. Just want to point that out.

By the way, they reported that empiric antibiotic use in patients without positive results for microbiological tests was not associated with a benefit. We did not see improved 30-day mortality or improved inpatient mortality, so not helpful. Seeing here about a doubling of bacterial co-infection in patients that got those early unnecessary antibiotics. You actually doing harm. I think we’ve said this several times, you’re doing harm if you give antibiotics in the first week for a viral infection when they don’t have a bacterial co-infection.

COVID early inflammatory, lower respiratory hypoxic phase. We need a code for this that we know. I think this is a better indicator of what’s going on. How many folks are getting hospitalized for COVID with a requirement for supplemental oxygen, steroids at the right time, anticoagulation, pulmonary support, remdesivir, if not on a ventilator. We’ll be discussing in a little more detail next week. Tocilizumab now is approved, not just EUA but actually has the indication for COVID.

COVID the late phase. That’s where we’re getting in our show here. A question we often get is regarding timing of surgery after COVID. The article, “Association of Time to Surgery After COVID-19 Infection With Risk of Post-Operative Cardiovascular Morbidity,” published in JAMA Network Open, suggests a reduction in complications once we get to about 100 days out. Really nice figure. These results were obtained from a single-center retrospective cohort study conducted among almost 4,000 adult patients.

Previous diagnosis of COVID-19 primary outcome was the composite occurrence of major cardiovascular comorbidity, defined as DVT, pulmonary embolism, cardiovascular accident, myocardial injury, kidney injury, and death within 30 days after surgery. You really see a nice drop in the incidence of these composite outcome just giving it that three months out. Now this theme seems to be getting reinforced as we get more information.

The article, “Demonstration of Stable Clusters of Symptoms in Long COVID,” published in OFID. This group previously demonstrated distinct phenotypes of Long COVID, but the impact of later waves caused by SARS-CoV-2 variants on Long COVID presentations. Here they present again, recurrent, a three-symptom clusters defining Long COVID, a musculoskeletal pain symptom cluster, a cardiorespiratory cluster, and a third less symptomatic cluster, different clusters over time, with characteristics of the cardiorespiratory phenotype evolving over time.

I also like the article, “Longitudinal Analysis of T-cells in COVID-19 Survivors with Post-Acute Sequelae of COVID-19 Reveals Association Between Individual Symptoms and Inflammatory Indexes,” published in OFID. As we discussed above, it is simplistic to think of the immune system as only B-cells and antibodies versus T-cells. Here, instead T-cells will save us. We see the suggestion that T-cells are actually causing trouble.

Their investigation demonstrated in this cohort participants who reported persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of CD8⁺Ki67⁺ cells. Those with dyspnea also had significantly higher levels of CD8⁺CD38⁺, CD38, CD8⁺Granzyme B⁺, and CD8⁺IL10⁺ cells. Those who suffered from forgetfulness, chest pain, and joint pain had significantly higher levels of the CD4⁺CD25⁺ cells.

A bit complex to go through all these cell types. To, again, oversimplify after I said we shouldn’t do that, these findings suggest an ongoing T-cell activation and an increase in T regulatory cells in an ongoing attempt to control ongoing host inflammation.

I will close with a shout out for the LISTEN Study, the Listen to Immune Symptom and Treatment Experiences Now Study. I don’t know who comes up with that, but the purpose of the study is to understand Long COVID, post-vaccine adverse events. Not just Long COVID, but folks having issues post-vaccine and the corresponding immune responses by collecting information about symptoms, medical history from participants who are members of a patient community, and by collecting blood and saliva samples from some participants. I’ve got a link here in the show notes. These are our colleagues up at Yale, so Akiko and Harlan Krumholz.

Then as I like to always close, no one is safe until everyone is safe. I would like folks to pause right here, go to parasiteswithoutborders.com, click on the “Donate” button. Maybe you can even get your family members listening, maybe that rich uncle who wants that feel-good, that Christmas cheer here. Go ahead and donate. Every small amount helps. During the rest of this month and all through January, donations to Parasites Without Borders will be matched and doubled up to a potential maximum donation of $40,000 to MicrobeTV.

VR: Yes, this is the time of year to get your support in for us. It’s our big fundraiser. It helps us do our work throughout the year. It’s time for your questions for Daniel. You can send yours to [email protected]. Donna writes, “I hope by the time I have an answer for this, it’s a moot point, but for the moment, my son’s 17 with asthma controlled well by a 2x daily inhaler of RediHaler. Has only had the first two vaccinations in 2021, and late 2021 he became needlephobic while using DUPIXENT for eczema. He could not do his fourth dose. We’ve been working with docs and psychologist since then.

He’s been in intensive therapy for anxiety since February, but it has brought us down this rabbit hole of avoidance behavior, and he has still not received booster shots or a flu shot. We are outside of Boston in a community highly vaccinated. Should he be wearing a mask? Should he mask in certain situations?”

DG: This is challenging. Let me recap of, I’ll say what I’m saying. We do think the science supports that it is ideal to at least get those three first shots. This is probably not a two-shot vaccine. It’s probably a three-shot vaccine. We really don’t know how important getting additional shots are in different groups. We clearly talk about the elderly. Elderly people with multiple medical problems. Yes, we really encourage them to get the booster shots based on what we know from the science.

You mentioned asthma. Interesting enough, early on, I would’ve thought asthma was going to be a risk factor for severe disease. Asthmatics, actually, tend to do fine, which is interesting, just put that in context. If your son is a lower risk individual, how important it is for them to get this bivalent booster if they’re needlephobic. I’m not sure it’s that important. I think that’s something that you can have a discussion with, with your provider about.

Should people be wearing masks during this horrible respiratory season? Actually, for your son, I’m a little bit more worried about the other respiratory viruses, human metapneumovirus, influenza, things like that. I think that that’s reasonable. You’re going to have to have a discussion there with your son. If you’re in a situation where they’re potentially at risk of getting a respiratory virus that was going to trigger an asthma exacerbation, certainly, it makes sense to do what you can to lower that risk.

VR: David writes, “Paxlovid is under the tree a gift from physicians to thee, no nostrum exotic or antibiotic. We wish you peace, love and ID.”

DG: I like that.

VR: Thanks for a great podcast. I always listen.” That’s from David Clement, MD from Carolina Internal Medicine. Thank you for the poem. Dan writes, “A friend of mine, female, has been testing antigen positive for three months. She’s twice vaccinated, has had COVID twice, has a variety of medical conditions, takes a variety of drugs, has fibromyalgia for 20 years. My questions are, how common is it for someone to be testing positive for so long?

Could she still be infectious? Are there clinical consequences? What can she do? The NHS here in the UK is fobbing her off as she mostly feels OK. It’s really hard to get an ID specialist unless you’re really sick here. My parents can’t get Paxlovid. It seems the NHS doesn’t give it to elderly-elderly or people with severe high risk comorbidities, which is very frustrating.” What about this long-term antigen persistence, Daniel?

DG: We certainly see this. What is the percentage? I don’t think we have a good number. It’s less than 1%, I’ll put it there. We certainly see people continue to antigen-test positive. In general, we don’t have a suggestion that these people continue to be Typhoid Marys, to bring up one of my distant Irish ancestors. Getting a handle on this, if you could actually get a PCR with a CT value that might give you some sense. Is it someone with a CT value of about 40? Is there just a tiny amount still there? You’re measuring antigen with the antigen test.

Now, I’m telling you to measure nucleic acid with a PCR. I think that that would be a reasonable thing to at least get some sense of what’s going on here. I don’t know if you need an ID specialist to do that or if this is something that could just be done otherwise. Do I suspect this person is continuing to transmit and spread to others? Not from what you’re telling me.

VR: I got an email today from a clinical immunologist in Germany who has patients, children with inborn errors of immunology. He says they are antigen-positive for months and months. He says he’s trying to get people to do plaque assays, but nobody wants to do a plaque assay. They all want to do PCR.

[laughter]

I know there are some people here in New York that do plaque assay, so I’m trying to hook him up with them because that would, that’s the experiment to do. Do a plaque assay, see if there’s any infectious virus there.

DG: Yes. Then also to follow, people around this individual, are they turning positive?

VR: That too. Yes, that would be very good. Household contacts of people who were antigen-positive for months. Those are good studies. Eric writes, “I was recently prescribed a five-day course of prednisone, 40 mgs. I’m in my late 40s. How would a short course affect your immune response? If I get infected with SARS-CoV-2 or influenza, should I seek antivirals? For how long of a period after taking steroids? I’m up to date on all my vaccines.”

DG: A short course, five days like that, I would have limited concerns. If someone’s on steroids when they get infected or they get infected and you put them on steroids, that’s when we’re seeing the issues.

VR: Lastly from Jenny. “I’m on Evusheld and have an upcoming appointment for my next shot. I called my doctor and asked if I should still come in given it isn’t effective for the current variants and has potential adverse effects. He said I should still get it as it still retains efficacy prophylactically. Now, I’m just confused. I keep reading it’s inactive against the new sub-variants. Do you know why he says it’s still effective? What am I missing?”

DG: This is a challenge. Maybe I’ll relate to it. Looking at neutralizing antibodies that would suggest that Evusheld lacks neutralizing antibody. This was designed as a neutralizing antibody therapy. This isn’t saying, “Oh, I’ve been vaccinated and the rest of my orchestra of immune players can come to bear.” This is supposed to be a neutralizing antibody. It’s been tested. It’s not a neutralizing antibody in the current environment so yes, I’ve stopped giving folks Evusheld.

The EUA is still out there, but as we’ve learned until they remove the EUA and actually take all the doses of Evusheld and get them out of the hands of clinicians, they will continue to be used.

VR: That’s TWiV weekly clinical update with Dr. Daniel Griffin. Thank you, Daniel.

DG: Thank you. And everyone, Merry Christmas and be safe.

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